The overall objective of the proposed research is to define essential characteristics of serotonergic neurons and to understand as fully as possible how these neurons interact with other neurons in a simple neural system. We have accumulated evidence to support the hypothesis that the mammalian enteric nervous system contains serotonergic neurons. We are now studying these neurons in the enteric nervous system, where their accessibility and the relative simiplicity of the system makes their analysis less complex than that of similar neurons in the central nervous system. In addition to continuing to study the properties of the enteric serotonergic neurons. We have also examined their phylogeny, their distribution in the gut, and their disposition in ganglionic and aganglionic regions of the colon in human and murine megacolon. The relationship of serotonergic neurons to other identified neurons to other identified neurons and their processes in the enteric nervous system will be defined. Finally, the characteristics of the enteric nervous system itself, such as the blood-myenteric plexus barrier, the nature of neurons that may utilize polypeptide neurotransmitters, and synaptic relationships between adrenergic and cholinergic elements will also be examined. Thus, we hope to further our understanding of this system, not only to learn about the regulation of gastrointestinal motility, but to develop a model system, the investigation of which will provide information generally useful for the study of the nervous system. The brain-like characteristics of the myenteric plexus, not found elsewhere in the peripheral nervous system, suggest that it will be particularly valuable in this role as a model.